SOMATIC MOSAICISM IN SPERM IS ASSOCIATED WITH INTERGENERATIONAL (CAG)(N) CHANGES IN HUNTINGTON DISEASE

We have analysed the CAG repeat in the Huntington disease (HD) gene in sperm and blood from 20 unrelated HD patients. Although the CAG repea t displayed significant mosaicism in sperm from all individuals, there were marked differences in the degree of repeat instability. Individu als who had either inherited or transmitted an expanded CAG repeat dis played the highest revels of repeat mosaicism, whereas individuals who had inherited or transmitted a contracted repeat had very limited CAG mosaicism in sperm. A strong association between intergenerational ch ange in CAG allele size and the level of sperm repeat mosaicism was de termined (P = 0.019). In contrast, neither blood CAG size nor repeat m osaicism in blood, were significantly associated with intergenerationa l CAG changes. These data suggest the presence of a cis-acting factor, separate from CAG size, that strongly influences the intergenerationa l behaviour of the CAG repeat. Additional studies are needed to determ ine whether analysis of CAG mosaicism in sperm is useful for assessing an individual's risk for transmitting large expansions or contraction s to his offspring.